Amino and carboxylterminal interaction

A unique property of the AR in the regulation of gene expression is its ability to provide intra-domain interaction and communication between the amino- and the carboxyl-terminal domains of the receptor (Langley etal. 1995; 1998; He etal. 1999). This interaction is mediated through a FXXLF and WXXLF motifs at amino acids 23-27 and 429-439 in the NH2-terminus of the receptor with distinct regions in the HBD of the AR (He et al. 2000). Interaction between NH2- and COOH-termini of the AR was shown to be necessary for the testosterone-induced AR stabilization and an antiparallel arrangement of AR monomers in the AR dimer (Berrevoets etal. 1998; Ikonen etal. 1997; Langley etal. 1995; 1998). The WXXLF motif has a significant but more minor role than the FXXLF motif in mediating the NH2-/COOH- interaction (He et al. 2000). The activity of the more relevant FXXLF motif is further modulated by its flanking sequences (Steketee et al. 2002).

Recently it was demonstrated that interaction of the NH2- and COOH-termini of the AR is essential for the recruitment of coactivator proteins SRC1, TIF2 and CBP (Saitoh etal. 2002). The importance oftheNH2-/COOH- terminal interaction was demonstrated in a mutational analysis of the AF2 domain of the AR, which showed that disruption of the functional interaction between NH2- and COOH-termini of the AR is linked to androgen insensitivity syndrome (Thompson et al. 2001). Intriguingly promoter-specific differences exist in the requirements of the NH2/COOH- interaction of the AR. While agonist-dependent transactivation of prostate-specific antigen (PSA) and probasin enhancer/promoter regions require the NH2-/COOH- interaction, the sex-linked protein gene and mouse mammary tumor virus long terminal repeat do not (He et al. 2002). At present there are no evident predictive features that differentiate these enhancer/promoter androgen response elements in terms of their sensitivity to the NH2-/COOH- interaction.

The NH2- and COOH-terminal interaction is in itself a regulated process. While the coactivators such as SRC-1 (Ikonen etal. 1997; He etal. 1999) TIF2 (Berrevoets etal. 1998), CREB-bindingprotein (Ikonen etal. 1997) and c-Jun (Bubulya etal. 2001) positively mediate this interaction, other proteins such as the tumor suppressor protein p53 exert a negative effect on transactivation of the AR by disrupting its NH2-/COOH- terminal interaction. Consistent with this, p53 is able to block DNA binding by the AR (Shenk etal. 2001). The negative effect of p53 is however blocked by overexpression of c-Jun, demonstrating antagonistic activities of these two proteins (Shenk etal. 2001). A p53 mutation found in metastatic prostate cancer severely disrupts the negative effect of p53 on the AR which would suggest that the inability of p53 mutants to downregulate the activity of the ARE may contribute to the metastatic phenotype (Shenk etal. 2001)

Hair Loss Prevention

Hair Loss Prevention

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